Note: Descriptions are shown in the official language in which they were submitted.
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METHODS OF SYNTHESIZING OLANZAPINE
RELATED US APPLICATION DATA
This application claims the benefit of U.S. provisional application No.
60/532,126, filed December 22, 2003; U.S. provisional application No.
60/547,901, filed
February 25, 2004; and U.S. provisional application No. 60/561,871, filed
April 12, 2004.
FIELD OF THE INVENTION
The invention encompasses methods of synthesizing olanzapine without solvents
or by using low boiling organic solvents.
BACKGROUND OF THE INVENTION
Olanzapine is an antagonist of D-1 and D-2 dopamine receptors and also
exhibits
antimuscarinic and anticholinergic properties and antagonist activity at SHT-2
receptor
sites. Olanzapine also acts as an antagonist of noradrenergic alpha-receptors.
These
properties indicate that olanzapine may possess relaxant, anxiolytic, or anti-
emetic
properties and may be suitable for use as an a neuroleptic. Olanzapine is
therefore useful
in treating psychotic conditions including schizophrenia, schizophreni-form
diseases, and
acute mania. Olanzapine can additionally be used in the treatment of mild
anxiety states
when administered at lower doses.
Clinical evaluations of psychiatric patients suffering from schizophrenia have
shown that olanzapine exhibits high levels of activity at surprisingly low
dosage levels,
making it a highly desirable therapeutic candidate for the treatment of
psychotic patients.
Unfortunately, olanzapine typically exhibits a color which is undesirable for
commercial
pharmaceutical use, especially as the color changes over time on exposure to
air.
The current methods of synthesizing olanzapine require harsh reaction
conditions,
such as high temperatures and/or strong bases, such as alkyl lithium bases,
with catalysts
which may contribute to the undesirable color changes. To achieve the high
reaction
temperatures necessary in the current methods of synthesizing olanzapine, high
boiling
solvents that are difficult to remove once the product is obtained are used.
U.S. Patent No. 5,229,382 discloses olanzapine synthesis by condensation of
thienobenzodiazepine (4-amino-2-methyl-lOH-thieno-[2,3-b] [1,5]benzodiazepine)
and
N-methylpiperazine in a mixture of toluene and dimethylsulfoxide, which are
high boiling
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organic solvents. The yield of the process is relatively low, and the solvent
recovery is
very difficult.
The invention encompasses methods of synthesizing olanzapine that do not
require high boiling solvents or high temperatures.
SLTMMARY OF THE INVENTION
One embodiment of the invention encompasses a method of synthesizing
olanzapine under neat conditions, comprising heating a reaction mixture of N-
methylpiperazine and thienobenzodiazepine (TBD) to about 110°C to about
145°C;
maintaining the reaction mixture at about 110°C to about 145°C
for at least 5 hours until
olanzapine is synthesized; cooling the reaction mixture; adding water, at
least two organic
solvents, or water and at least one organic solvent, until olanzapine
precipitates; and
collecting the precipitated olanzapine. Optionally, the process may include
further
cooling steps.
The invention also encompasses methods of synthesizing olanzapine comprising
combining TBD with N-methylpiperazine in a low boiling organic solvent to form
a
reaction mixture; heating the reaction mixture at reflux temperature for about
20 to about
24 hours; cooling the reaction mixture; adding water to the reaction mixture
until
olanzapine precipitates; and collecting olanzapine.
The methods of the invention may further comprise purging the reaction mixture
during heating.
DETAILED DESCRIPTION OF THE INVENTION
The invention encompasses methods for synthesizing olanzapine using either no
solvent or easily recoverable low boiling organic solvents and moderate
reaction
temperatures wherein solvent recovery is relatively simple. "Low boiling
organic
solvents" are pharmaceutically acceptable solvents with boiling points less
than about
120°C, and preferably with boiling points less than about 100°C.
Preferred low boiling
organic solvents are those with boiling points between about 40°C to
about 120°C, and
more preferably are those solvents with boiling points between about
50°C to about 90°C.
Preferred low boiling organic solvents include acetonitrile, which has a
boiling point of
about 81 °C to about 82°C and is more environmentally friendly
than the solvents used in
the prior art. Another preferred low boiling organic solvent is acetone, which
has a
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boiling point of about 56°C. It has been found that the lack of high
boiling organic
solvents increases the purity of crude olanzapine, simplifies the synthesis of
olanzapine,
and diminishes the potential for undesirable color changes upon exposing
olanzapine to
air.
During the synthesis of olanzapine, the reaction mixture may be purged with
gas.
Purging gas through the reaction mixture during heating mixes the reaction
mixture and
removes compounds which may become impurities in the final product, yielding
olanzapine with fewer impurities, and thus, simplifying the purification
process. For
example, removing ammonia from the reaction mixture by purging yields
olanzapine with
fewer by-products, thereby simplifying the purification process.
Thienobenzodiazepine (TBD) used in the invention refers to 4-amino-2-methyl-
lOH-thieno-[2,3-b] [1,5]benzodiazepine. TBD may be present as the
hydrochloride acid
salt or another stable acid salt. Preferably, TBD is present as
thienobenzodiazepine
hydrochloride. Thienobenzodiazepine may be present in the reaction mixture as
the
stoichiometrically limiting reagent. N-methylpiperazine is present in excess
in the
reaction mixture.
One embodiment of the invention encompasses a method of synthesizing
olanzapine under neat conditions, comprising heating a reaction mixture of N-
methylpiperazine and TBD to about 110°C to about 145°C;
maintaining the reaction
mixture at about 110°C to about 145°C for at least five hours
until olanzapine is
synthesized; cooling the reaction mixture; adding water, at least two organic
solvents, or
water and at least one organic solvent to precipitate olanzapine; and
collecting the
olanzapine.
TBD may be added after N-methylpiperazine is heated. Typically, the molar
ratio
of thienobenzodiazepine hydrochloride to N-methylpiperazine is about 1:3 to
about 1:8,
and preferably, the molar ratio is about 1:8. Preferably, the reaction mixture
is heated
under a nitrogen atmosphere. The reaction mixture is typically maintained at
about
110°C to about 145°C for about 5 to about 6 hours, and
preferably for about 5 hours.
The mixture is preferably heated at about 125°C. Preferably, the
reaction mixture is
purged during heating by bubbling gas through the reaction mixture.
Preferably, the gas
is nitrogen gas and more preferably the gas is dry nitrogen gas.
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The reaction mixture is preferably cooled to a temperature of less than about
100°C, more preferably to about room temperature to about 80°C,
and most preferably to
about 80°C.
Preferred organic solvents used to precipitate olanzapine include at least one
of
acetone, acetonitrile, tetrahydrofuran (THF), toluene and DMSO. When two
organic
solvents are used, the ratio of the two solvents is about 1:2 to about 1:10 by
volume. The
solvents may be added either concurrently or consecutively, e.g., at once or
dropwise.
One of ordinary skill in the art can easily determine the amount of solvents
and water
necessary to induce olanzapine precipitation with little or no
experimentation.
Optionally, the process may include further cooling steps after adding water,
at
least two organic solvents, or water and at least one organic solvent,
comprising
graduated cooling of the reaction mixture to temperatures ranging from about
70°C to
about -5°C. Preferably, further cooling steps comprise cooling the
reaction mixture to
about 70°C to below 10°C, more preferably to about 70°C
to about 0°C, even more
preferably to about 70°C to about 50°C, and most preferably to
about 70°C to about
60°C.
The reaction mixture may optionally be stirred overnight before collecting
olanzapine. Olanzapine may be separated and collected from the reaction
mixture using a
variety of techniques known to the skilled artisan, e.g., by filtration or
decantation.
Another embodiment of the invention encompasses methods of synthesizing
olanzapine comprising combining TBD with N-methylpiperazine in a low boiling
organic
solvent to form a reaction mixture; heating the reaction mixture to about
reflux
temperature for about 20 to about 24 hours until olanzapine is synthesized;
cooling the
reaction mixture; adding water until olanzapine precipitates; and collecting
olanzapine.
Typically, the molar ratio of TBD to N-methylpiperazine is about 1:3 to about
1:8.
Preferred low boiling organic solvents which may be used in this method
include, but are
not limited to, acetone, acetonitrile, hexane, heptane and dimethylformamide.
The
reaction mixture may be purged during heating. Preferably, olanzapine is
synthesized in
about 22 hours. Preferably, the reaction mixture is cooled to about
22°C to about 28°C.
Water is added to the reaction mixture in an amount sufficient to induce
precipitation of olanzapine. One of ordinary skill in the art can easily
determine the
amount of water necessary to induce olanzapine precipitation with little or no
experimentation. Factors that must be considered include the low boiling
organic solvent
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used, the volume of low boiling organic solvent, the reaction amount, and
other factors
typically affecting the scale of the reaction. After the addition of water,
the reaction
mixture may be further cooled to about 10°C to about -5°C. The
precipitated olanzapine
may be separated and collected from the reaction mixture using a variety of
techniques
known to the skilled artisan.
Having described the invention with reference to certain preferred
embodiments,
other embodiments will become apparent to one skilled in the art from
consideration of
the specification. The invention is further defined by reference to the
following examples
describing in detail the compositions, preparation of the compositions, and
methods of
administration of the invention. It will be apparent to those skilled in the
art that many
modifications, both to materials and methods, may be practiced without
departing from
the scope of the invention.
EXAMPLES
Example l:
Thienobenzodiazepine hydrochloride (TBD, 8.6 g, 32.3 mmol),
N-methylpiperazine (30 ml, 27.1 g, 270 mmol), and acetone (30 ml) were added
to a 100
ml round bottom flask equiped with a magnetic stirrer and a reflux condenser,
forming a
reaction mixture. The reaction mixture was heated to reflux (about
56°C) under a
nitrogen atmosphere. After 22 hours, the reaction mixture was cooled to about
room
temperature. Water (30 ml) was added to the reaction mixture, and the reaction
mixture
was cooled in an ice bath until olanzapine precipitated. Olanzapine (5.2 g)
was collected
by filtration in a yield of 51 %, as determined by HPLC.
Example 2:
Thienobenzodiazepine hydrochloride (TBD, 8 g, 30 mmol), N-methylpiperazine
(15 ml, 13.5 g, 135 mmol), and acetonitrle (15 ml) were added to a 100 ml
round bottom
flask equiped with a magnetic stirrer and a reflux condenser and heated to
reflux (about
81-82°C) under a nitrogen atmosphere. After 22 hours, the reaction
mixture was cooled
to room temperature. Water (25 ml) was added to the reaction mixture. Upon a
precipitate forming, additional water was added (25 ml) until the precipitate
dissolved,
and the mixture was stirred for 30 min. Olanzapine (5 g) was collected by
filtration in a
yield of 53%, as determined by HPLC
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Example 3:
Thienobenzodiazepine hydrochloride (TBD, 8 g, 30 mmol), N-methylpiperazine
(10 ml, 9.02 g, 90 mmol), and DMSO (15 ml) were added to a 100 ml round bottom
flask
equiped with a magnetic stirrer and a reflux condenser, forming a reaction
mixture. The
reaction mixture was heated to reflux (about 138°C) under a nitrogen
atmosphere. After
22 hours, the reaction mixture was cooled to room temperature. Water (30 ml)
was added
to the reaction mixture and the mixture was cooled in an ice bath until
olanzapine
precipitated. Olanzapine (5.1 g) was collected by filtration in a yield of
54%, as
determined by HPLC
Example 4:
Thienobenzodiazepine hydrochloride (TBD, 8 g, 30 mmol), N-methylpiperazine
(10 ml, 9.02 g, 90 mmol), and acetone (16 ml) were added to a 100 ml round
bottom flask
equiped with a magnetic stirrer and a reflux condenser, forming a reaction
mixture. The
reaction mixture was heated to reflux (about 56°C) under a nitrogen
atmosphere. After
24 hours, the reaction mixture was cooled to room temperature, and a solid
formed.
Water (50 ml) was added to the solid, which became granular. Olanzapine was
collected
by filtration in a yield of 91.6%, as determined by HPLC.
Example 5:
In a 100 ml round bottom flask, N-methylpiperazine (9.75 ml, 8.8 g, 88 mmol)
was heated in an oil bath to 125°C under nitrogen for 10 min.
Thereafter,
thienobenzodiazepine hydrochloride (8 g, 30 mmol) was added to form a reaction
mixture. After 12 hours, the reaction mixture was cooled to room temperature.
Water
(12 ml) was added dropwise to the reaction mixture. Upon formation of a
precipitate,
additional water was added (12 ml) to the reaction mixture. The reaction
mixture was
stirred at room temperature. A granular solid formed and additional water (18
ml) was
added. Olanzapine was collected by filtration in a yield of 84%, as determined
by HPLC.
Example 6:
In a 100 ml round bottom flask, N-rnethylpiperazine (11 ml, 10 g, 100 mmol)
was
heated in an oil bath to 125°C under nitrogen for 10 min. Thereafter,
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thienobenzodiazepine hydrochloride (8 g, 30 mmol) was added to form a reaction
mixture. After 12 hours, the reaction mixture was cooled to 80°C.
Acetonitrile (20 ml)
was added slowly to the reaction mixture via a funnel, whereupon a precipitate
formed.
Additional acetonitrile (30 ml) was added until the precipitate dissolved. The
reaction
mixture was removed from the oil bath and cooled to room temperature while
stirring.
After 10 min. a crystalline solid precipitated and after 90 min, the reaction
mixture was
cooled in an ice bath. The solid was collected by filtration , washed in
acetonitrile, and
determined to be olanzapine by HPLC (4.53 g, 93.3% yield).
Example 7:
In a three necked flask, a reaction mixture of N-methylpiperazine (48 g, 480
mmol) and thienobenzadiazepine hydrochloride (16 g, 60 mmol) was heated in an
oil bath
to 125°C while stirring and purging for 5 hours. Thereafter, the
reaction mixture was
allowed to cool to 80°C and tetrahydrofuran (5 ml) and toluene (50 ml)
were added
separately. The reaction was stirred overnight, cooled in an ice bath for 1
hour, and a
precipitate formed. The precipitate was collected by filtration and dried for
2 hours under
vacuum, with pressure of less than 100 mm Hg, at 65°C and determined to
be olanzapine
by HPLC (91.5% yield).
Example 8:
In a three necked flask, a reaction mixture of N-methylpiperazine (30 g, 300
mmol) and thienobenzadiazepine hydrochloride (10 g, 37.6 mmol) was heated in
an oil
bath to 125°C while stirnng and purging for 5 hours. Thereafter, the
reaction mixture
was cooled to 80°C. Tetrahydrofuran (5 ml) was added to the reaction
mixture, and
toluene (32 ml) was added to the reaction mixture. The reaction was stirred
overnight at
room temperature (25°C to 27°C), cooled in an ice bath for 1
hour, and a precipitate
formed. The precipitate was collected by filtration and washed (2 x THFaoluene
5:32).
The precipitate was then dried for 2 hours under vacuum at 65 °C and
determined to be
olanzapine by HPLC (88.8% yield).
Example 9:
In a three necked flask, a reaction mixture of N-methylpiperazine (96 g, 960
mmol) and thienobenzadiazepine hydrochloride (32 g, 120 mmol) was heated in an
oil
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bath to 125°C while stirnng and purging for S hours. Thereafter, the
reaction mixture
was allowed to cool to 80°C and toluene (100 ml) was added followed by
dropwise
addition of water (50 ml). The reaction mixture was stirred overnight at room
temperature, cooled in an ice bath for 1 hour, and a precipitate formed. The
precipitate
was collected by filtration and washed (2 x toluene:water 2:1). The
precipitate was then
dried for 2 hours under vacuum at 65°C and determined to be olanzapine
by HPLC (91
yield).
Example 10:
In a three necked flask, a reaction mixture of N-methylpiperazine (150 g, 1.5
mol)
and thienobenzadiazepine hydrochloride (50 g, 0.188 mol) was heated in an oil
bath to
145°C while stirnng and purging for 1.5 hours at a gentle reflux, and
then for an
additional 4.5 hours. The reaction mixture was monitored by HPLC until only
0.18% of
thienobenzadiazepine remained. Thereafter, the reaction mixture was cooled to
below
100°C and toluene (200 ml), dimethylsulfoxide (200 ml) and water (200
ml) were added.
The reaction mixture was cooled to 70°C. The reaction mixture was
further cooled to
50°C, and a precipitate formed. The reaction mixture was stirred
overnight at room
temperature, cooled in an ice bath for 1 hour, and a precipitate formed. The
precipitate
was collected by filtration and washed (2 x water, 40 ml). A wet solid was
collected
(66.2 g) and then dried overnight under vacuum at 65°C to yield
olanzapine (49.3 g,
85%).
The wet solid collected (5 g) was mixed in acetonitrile (36 ml) and water (22
ml)
and heated to 80°C until the material dissolved, forming a solution.
The solution was
cooled, and a precipitate formed. The solution was left to sit overnight. The
solution was
cooled in an ice bath, filtered, and the precipitate was collected by
filtration. The
precipitate was dried overnight under vacuum at 65°C, and determined to
be olanzapine
in 99.5% purity, by HPLC.
Example 11:
Thienobenzodiazepine hydrochloride (50 g) and N-methylpiperazine (150 g)
were added to a 1 liter reactor equipped with a mechanical stirrer, condenser,
and
thermometer, to form a reaction mixture. The reaction mixture was heated to
125°C for
five hours and cooled to 80°C. DMSO (200 ml) and toluene (200 ml) were
added. The
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reaction mixture was cooled further to 60°C and 200 ml of water was
added. The
reaction mixture was cooled further to 10°C for 2 hours and heated to
50°C for 2 hours.
The reaction mixture was cooled to 10°C and heated to 50°C in
the manner above two
more times. The reaction mixture was cooled to 10°C and stirred for 2
hours. A slurry
resulted. The slurry was filtered under vacuum and washed with toluene (100
ml) and
water (150 ml) and determined to be olanzapine (~O.Sg, 99.5% purity) by HPLC.
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